Identification of Germline Monoallelic Mutations in IKZF2 in Patients with Immune Dysregulation
Sprache des Titels:
Englisch
Original Kurzfassung:
Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal
roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are
frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3, encoding
Ikaros and Aiolos, have recently been identified in patients with phenotypically similar
immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and
immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4
distinct missense variants) in six patients with systemic lupus erythematosus, immune
thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited
hypogammaglobulinemia, decreased number of T-follicular helper and NK-cells. Single-cell RNA
sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of pro-
inflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional
assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover,
proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of
3/5 Helios mutants with core components of the NuRD complex conveying HELIOS-mediated epigenetic
and transcriptional dysregulation.
Forschungs-